Progress and challenges in protein structure prediction

Abstract

Depending on whether similar structures are found in the PDB library, the protein structure prediction can be categorized into template-based modeling and free modeling. Although threading is an efficient tool to detect the structural analogs, the advancements in methodology development have come to a steady state. Encouraging progress is observed in structure refinement which aims at drawing template structures closer to the native; this has been mainly driven by the use of multiple structure templates and the development of hybrid knowledge-based and physics-based force fields. For free modeling, exciting examples have been witnessed in folding small proteins to atomic resolutions. However, predicting structures for proteins larger than 150 residues still remains a challenge, with bottlenecks from both force field and conformational search.

Figure 1

Structural superimposition results of 1413 representative single-domain proteins on their analogs in the PDB library. The structural analogs are searched by a sequence-independent structural-alignment tool, TM-align [8], and ranked by TM-score (a structural similarity measure balancing rmsd and coverage) [51]. All structural analogs with a sequence identity >20% to the target are excluded. If the analog of the highest TM-score has a coverage below 70%, the first structural analog with the coverage >70% is presented. As a result, all the structural analogs have a rmsd < 6 Å; 80% have a rmsd < 4 Å with >75% regions covered.

Figure 2

Representative examples of free modeling in CASP7 generated by two different approaches. T0283 (left panel) is a TBM target (from Bacillus halodurans) of 112 residues; but the model is generated by all-atom ROSETTA (a hybrid knowledge-based and physics-based approach) [45•] based on free modeling, which gives a TM-score 0.74 and a rmsd 1.8 Å over the first 92 residues (the overall rmsd is 13.8 Å mainly because of the misorientation of C-terminal). T0382 (right panel) is a FM/TBM target (from Rhodopseudomonas palustris CGA009) of 123 residues; the model is generated by I-TASSER (a purely knowledge-based approach) [31••] with a TM-score 0.66 and a rmsd 3.6 Å. Blue and red represent the model and the crystal structure, respectively.